Method for the production of fluoromethyl-substituted heterocycles

ABSTRACT

The present invention relates to a process for preparing fluoromethyl-substituted heterocycles of the formula (I)  
                 
         in which R 1 , R 2 , R 3  and A are each as defined in the disclosure, by fluorinating the corresponding chloromethyl-substituted precursors.

The present invention relates to a novel process for preparing fluoromethyl-substituted heterocycles by reacting the corresponding chloromethyl-substituted compound with a fluorinating agent.

It is already known that 3-(difluoromethyl)- and 3-(fluorodichloromethyl)-1-methyl-1H-pyrazole-4-carboxylic esters can be obtained by reacting the correspondingly halogenated 2-(ethoxymethylene)methyl acetoacetate with methylhydrazine (cf. WO 92/12970 and WO 93/11117).

It is also known that 5-chloropyrazole-4-carboxaldehyde derivatives can be reacted with potassium fluoride in dimethylformamide to give the corresponding 5-fluoro compound (cf. WO 93/11117).

The conversion of heterocycles which are substituted by mono-, di- or trichloromethyl to fluorinated analogues is known hitherto only for pyridine derivatives. Since chlorinated precursors are frequently more readily available than the corresponding fluorine compounds for the preparation of heterocycles, there is a need for a process which allows chlorinated heterocycles to be directly fluorinated.

The present invention thus provides a process for preparing fluoromethyl-substituted heterocycles of the formula (I)

in which

-   R¹ is hydrogen, fluorine or chlorine, -   R² is hydrogen, fluorine or chlorine, -   R³ is C₁-C₆-alkyl, -   A is 5-membered heterocycle selected from the group of pyrazole     which is substituted by R⁴ in the 1-position, thiazole which is     substituted by R⁴ in the 2-position and oxazole which is substituted     by R⁴ in the 2-position, -   R⁴ is C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-alkylthio-C₁-C₄-alkyl,     C₁-C₄-alkoxy-C₁-C₄-alkyl or phenyl,     characterized in that -   a) chloromethyl-substituted heterocycles of the formula (II)     -    in which R¹, R², R³ and A are each as defined above are         converted in the presence of a fluorinating agent and optionally         in the presence of a diluent.

Surprisingly, the fluoromethyl-substituted heterocycles of the formula (I) can be prepared with good yields in high purity and selectivity under the inventive conditions. Although the preparation of trifluoromethyl-, difluoromethyl- or monofluoromethyl-substituted aromatic compounds from the correspondingly chlorinated compounds by halogen exchange is known for phenyl- and some 3-trihaloalkylpyridine derivatives, it is necessary in these processes to employ severe conditions such as the use of HF, high temperatures and pressure. Under these reaction conditions, those skilled in the art, in the case of pyrazole, thiazole and other heterocyclic compounds which are substituted by trichloromethyl or by the more sensitive and less stable dichloromethyl, would expect the decomposition of the heterocycle (for example by polymerization, hydrolysis or the formation of acids and aldehydes). This decomposition process is even accelerated when, for example, a dichloromethyl group is conjugated directly with an electron pair of a nitrogen atom, as is the case for 3-haloalkyl-substituted pyrazoles. In addition, the fluorination of compounds having a substituent in the ortho-position, especially when it is the large and electron-withdrawing carboxylic ester group, is distinctly more difficult to carry out for steric and electronic reasons. This is because the carboxylic ester group is normally hydrolysed under strongly acidic conditions (for example when HF or its derivatives are used) and forms a ring with the adjacent trichloromethyl or dichloromethyl group: It is all the more surprising that the fluoromethyl-substituted heterocycles of the formula (I) can be obtained in good yields by the process according to the invention.

When, for example, ethyl 3-(dichloromethyl)-1-methyl-1H-pyrazole-4-carboxylate is used as a starting material and triethylamine (tris)hydrofluoride as the fluorinating agent, the process according to the invention (a) may be illustrated by the following scheme.

The chloromethyl-substituted heterocycles used as starting materials when carrying out the process according to the invention are generally defined by the formula (II). The substituents have the following preferred definitions:

-   R¹ is preferably hydrogen, fluorine or chlorine. -   R² is preferably hydrogen, fluorine or chlorine. -   R³ is preferably C₁-C₄-alkyl, more preferably methyl, ethyl,     n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl,     most preferably methyl or ethyl. -   A is preferably a 5-membered heterocycle selected from the group of -    more preferably a 5-membered heterocycle selected from the group of -    most preferably a 5-membered heterocycle selected from the group of -    where in each case the bond marked by * is joined to the —CClR¹R²     group and the other bond to the ester group, -   R⁴ is preferably methyl, ethyl, n-propyl, isopropyl, cyclopropyl,     cyclopentyl, cyclohexyl or phenyl, more preferably methyl, ethyl,     isopropyl or phenyl, most preferably methyl.

The starting material used is preferably a chloromethyl-substituted heterocycle of the formula (II) in which R¹ is chlorine and R² is hydrogen.

Particularly preferred starting materials of the formula (II) are chloromethyl-substituted heterocycles of the formula (II-a)

in which R¹, R² and R³ are each as defined above.

Very particular preference is given to compounds of the formula (II-a) in which R¹ is chlorine, R² is hydrogen and R³ is methyl or ethyl.

Particularly preferred starting materials of the formula (II) are likewise chloromethyl-substituted heterocycles of the formula (II-b)

in which R¹, R² and R³ are each as defined above.

Very particular preference is given to compounds of the formula (II-b) in which R¹ is chlorine, R² is hydrogen and R³ is methyl or ethyl.

Particularly preferred starting materials of the formula (II) are likewise chloromethyl-substituted heterocycles of the formula (II-c)

in which R¹, R² and R³ are each as defined above.

Very particular preference is given to compounds of the formula (II-c) in which R¹ is chlorine, R² is hydrogen and R³ is methyl or ethyl.

Particularly preferred starting materials of the formula (II) are likewise chloromethyl-substituted heterocycles of the formula (II-d)

in which R¹, R² and R³ are each as defined above.

Very particular preference is given to compounds of the formula (II-d) in which R¹ is chlorine, R² is hydrogen and R³ is methyl or ethyl.

Some chloromethyl-substituted heterocycles of the formula (II) are known (cf. WO 92/12970, WO 93/11117 and The Chemistry of Heterocyclic Compounds: Thiazole and its derivatives, Jaques Metzger (ed.), Vol. 34, Part 1-3, John Wiley and Sons, New York, 1979).

3-Halomethyl-1H-pyrazole-4-carboxylic esters can be prepared by

-   b) reacting acid halides of the formula (III) -    in which     -   R¹ and R² are each as defined above,     -   Hal is fluorine, chlorine or bromine,     -   with dialkylaminoacrylic esters of the formula (IV)     -    in which     -   R³ is as defined above,     -   R⁵ and R⁶ are each independently C₁-C₄-alkyl in a         water-inmiscible organic solvent (for example toluene) in the         presence of a base (for example sodium hydroxide or pyridine),     -   and reacting the thus obtained 2-dihaloacyl-3-aminoacrylic         esters of the formula (V)     -    in which R¹, R², R³, R⁵ and R⁶ are as each as defined above         with hydrazine derivatives of the formula (VI)         R⁴—NH—NH₂  (VI)     -    in which R⁴ is as defined above in the presence of a diluent         (for example toluene).

The process (a) according to the invention is carried out in the presence of a fluorinating agent. Useful for this purpose are all customary fluorinating agents for such reactions. Preference is given to using, for example, alkali metal fluorides such as sodium fluoride, potassium fluoride and caesium fluoride, cobalt(III) fluoride, halogen fluorides, antimony fluorides, molybdenum fluoride, hydrogen fluoride, hydrogen fluoride/pyridine mixtures, tertiary ammonium hydrofluorides or trialkylamine hydrofluorides of the general formula n HF/N(Alk)₃ (where n is 1, 2, or 3, preferably 2 or 3, and Alk is C₁-C₄-alkyl, preferably ethyl or n-butyl). Particular preference is given to using 3 HF/N(Et)₃ (Franz reagent), 3 H/N(n-Bu)₃ and HF/pyridine (Olah's reagent). Very particular preference is given to using 3 HF/N(Et)₃ (Franz reagent) or 3 HF/N(n-Bu)₃.

The process according to the invention is optionally carried out in the presence of a diluent. Preference is given to using nitriles such as acetonitrile; halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane, trifluorochloromethane, 1,1,2-trifluoro-1,2,2-trichloroethane, 1,1,1-trifluoro-2,2,2-trichloroethane or trichloroethane; aromatic hydrocarbons, for example petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; diethylene glycol. Particular preference is given to using acetonitrile, toluene, chlorobenzene, trifluorochloromethane, 1,1,2-trifluoro-1,2,2-trichloroethane, 1,1,1-trifluoro-2,2,2-trichloroethane, dioxane or diethylene glycol.

When carrying out the process according to the invention, it is possible to work within a relatively wide temperature range. In general, working temperatures are 80° C. to 170° C. or in the range of 20° C. to 170° C., preferably 120° C. to 150° C. or 100° C. to 150° C.

The process according to the invention is generally carried out under atmospheric pressure, However, it is also possible to work under elevated or reduced pressure, generally between 0.1 bar and 50 bar, preferably between 1 bar and 10 bar.

The reaction time is not critical and may be selected depending on the batch size within a relatively wide range of 1 h to 20 h, preferably of 6 h to 12 h.

When carrying out the process according to the invention, for 1 mol of chloromethyl-substituted heterocycles of the formula (II), generally between 1 mol and 3 mol of bound HF, preferably between 1 mol and 1.5 mol, of fluorinating agent are used per chlorine atom.

The fluoromethyl-substituted heterocycles of the formula which can be prepared by the process according to the invention are valuable precursors for the preparation of halomethyl-substituted pyrazolyl-, thiazolyl- and oxazolylcarboxamides which constitute active fungicidal ingredients (cf. WO 03/070705).

For example, fungicidally active carboxamides of the formula (VII)

in which

-   R¹, R² and A are each as defined above, -   R⁷ is hydrogen, C₁-C₈-alkyl, C₁-C₆-alkylsulphinyl,     C₁-C₆-alkylsulphonyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl;     C₁-C₆-haloalkyl, C₁-C₄-haloalkylthio, C₁-C₄-haloalkylsulphinyl,     C₁-C₄-haloalkylsulphonyl, halo-C₁-C₄-alkoxy-C₁-C₄-alkyl,     C₃-C₈-halocycloalkyl having in each case 1 to 9 fluorine, chlorine     and/or bromine atoms; formyl, formyl-C₁-C₃-alkyl,     (C₁-C₃-alkyl)carbonyl-C₁-C₃-alkyl,     (C₁-C₃-alkoxy)carbonyl-C₁-C₃-alkyl;     halo-(C₁-C₃-alkyl)carbonyl-C₁-C₃-alkyl,     halo-(C₁-C₃-alkoxy)carbonyl-C₁-C₃-alkyl having in each case 1 to 13     fluorine, chlorine and/or bromine atoms; (C₁-C₈-alkyl)carbonyl,     (C₁-C₈-alkoxy)carbonyl, (C₁-C₄-alkoxy-C₁-C₄-alkyl)carbonyl,     (C₃-C₈-cycloalkyl)carbonyl; (C₁-C₆-haloalkyl)carbonyl,     (C₁-C₆-haloalkoxy)carbonyl, (halo-C₁-C₄-alkoxy-C₁-C₄-alkyl)carbonyl,     (C₃-C₈-halocycloalkyl)carbonyl having in each case 1 to 9 fluorine,     chlorine and/or bromine atoms; or —C(═O)C(═O)R¹⁰, —CONR¹¹R¹² or     —CH₂NR¹³R¹⁴, -   R⁸ is hydrogen, fluorine, chlorine, methyl, isopropyl, methylthio or     trifluoromethyl, -   n is 1, 2, 3 or 4, preferably 1 or 2, -   R⁹ is optionally mono- to pentasubstituted phenyl having identical     or different substituents which are selected from halogen,     C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₂-haloalkyl or C₁-C₂-haloalkoxy     having in each case 1 to 5 fluorine, chlorine and/or bromine atoms,     hydroxyimino-C₁-C₄-alkyl, C₁-C₄-alkoxyimino-C₁-C₄-alkyl,     C₁-C₄-haloalkoxyimino-C₁-C₄-alkyl, or, in the case of two adjacent     substituents, from difluoromethylenedioxy or     tetrafluoroethylenedioxy;     -   or is C₃-C₁₀-cycloalkyl or C₃-C₁₀-bicycloalkyl which is in each         case optionally mono- to tetrasubstituted, identically or         differently, by halogen and/or C₁-C₄-alkyl;     -   or unsubstituted C₂-C₂₀-alkyl, or C₁-C₂₀-alkyl which is mono- or         polysubstituted, identically or differently, by fluorine,         chlorine, bromine, iodine and/or C₃-C₆-cycloalkyl, in which case         the cycloalkyl moiety may itself optionally be mono- to         tetrasubstituted, identically or differently, by fluorine,         chlorine, bromine, iodine, C₁-C₄-alkyl and/or C₁-C₄-haloalkyl;     -   or is C₂-C₂₀-alkenyl or C₂-C₂₀-alkynyl which is in each case         optionally mono- or polysubstituted, identically or differently,         by fluorine, chlorine, bromine, iodine and/or C₃-C₆-cycloalkyl         in which case the cycloalkyl moiety may itself optionally be         mono- to tetrasubstituted, identically or differently, by         fluorine, chlorine, bromine, iodine, C₁-C₄-alkyl and/or         C₁-C₄-haloalkyl; -   R¹⁰ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxy,     C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl; C₁-C₆-haloalkyl,     C₁-C₆-haloalkoxy, halo-C₁-C₄-alkoxy-C₁-C₄-alkyl,     C₃-C₈-halocycloalkyl having in each case 1 to 9 fluorine, chlorine     and/or bromine atoms, -   R¹¹ and R¹² are each independently hydrogen, C₁-C₈-alkyl,     C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl; C₁-C₈-haloalkyl,     halo-C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-halocycloalkyl having in each     case 1 to 9 fluorine, chlorine and/or bromine atoms, -   R¹¹ and R¹² are also, together with the nitrogen atom to which they     are bonded, a saturated heterocycle having 5 to 8 ring atoms which     is optionally mono- or polysubstituted, identically or differently,     by halogen or C₁-C₄-alkyl, and the heterocycle may contain 1 or 2     further, nonadjacent heteroatoms from the group of oxygen, sulphur     and NR¹⁵, -   R¹³ and R¹⁴ are each independently nitrogen atom, C₁-C₈-alkyl,     C₃-C₈-cycloalkyl; C₁-C₈-haloalkyl, C₃-C₈-halocycloalkyl having in     each case 1 to 9 fluorine, chlorine and/or bromine atoms, -   R¹³ and R¹⁴ are also, together with the nitrogen atom to which they     are bonded, a saturated heterocycle having 5 to 8 ring atoms which     is optionally mono- or polysubstituted, identically or differently,     by halogen or C₁-C₄-alkyl, and the heterocycle may contain 1 or 2     further, nonadjacent heteroatoms from the group of oxygen, sulphur     and NR¹⁵, -   R¹⁵ is hydrogen or C₁-C₆-alkyl     are obtained by hydrolyzing fluoromethyl-substituted heterocycles of     the formula (I) -   in which R¹, R², R³ and A are each as defined above -   in the presence of a base and optionally in the presence of a     diluent, and subsequently either converting the free acid to the     corresponding acid chloride in the presence of a chlorinating agent     and optionally in the presence of a diluent or reacting the free     acid directly with aniline derivatives of the formula (VIII) -   in which R⁷, R⁸, n and R⁹ are each as defined above -   optionally in the presence of a catalyst, optionally in the presence     of a condensing agent, optionally in the presence of an acid binding     agent and optionally in the presence of a diluent.

The inventive preparation of fluoromethyl-substituted heterocycles of the formula (I) is described in the examples which follow, which further illustrate the above description. However, the examples should not be interpreted in a restrictive manner.

PREPARATIVE EXAMPLES Example 1

Ethyl 3-(dichloromethyl)-1-methyl-1H-pyrazole-4-carboxylate (37.9 g, 0.16 mol) and triethylamine tris(hydrofluoride) (80 g, 0.49 mol) were heated in an autoclave at 145° C. for 8 h. The reaction mixture was then diluted with 200 ml of water. The precipitated product was filtered off, washed and dried.

28.5 g (87% of theory) of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate having a melting point of 43-46° C. were obtained.

¹H NMR (CDCl₃): δ=1.35 (t, 3H); 3.96 (t, 3H); 4.31 (q, CH₂); 7.10 (t, CF₂H); 7.90 (s, 1H) ppm. ¹⁹F NMR (CDCl₃): δ=−117.2 (d, J=55.4 Hz) ppm.

Example 2

37.9 g (0.16 mol) of ethyl 3-(dichloromethyl)-1-methyl-1H-pyrazole-4-carboxylate and 80 g (0.49 mol) of triethylamine tris(hydrofluoride) were heated in an autoclave at 120° C. for 8 h. The reaction mixture was then diluted with 200 ml of water and the product extracted with ethyl acetate. The desired product was removed by chromatography from ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate and isolated.

20 g (56% of theory) of ethyl 3-(fluorochloromethyl)-1-methyl-1H-pyrazole-4-carboxylate were obtained.

¹⁹F NMR (CDCl₃): δ=−133.8 (d, J=47.5 Hz) ppm.

Example 3

37.9 g (0.16 mol) of ethyl 4-(dichloromethyl)-1-methyl-1H-pyrazole-3-carboxylate and 80 g (0.49 mol) of triethylamine tris(hydrofluoride) were heated in an autoclave at 160° C. for 8 h. The reaction mixture was then diluted with 200 ml of water and the product extracted with ethyl acetate. The desired product was purified by chromatography and isolated.

26.8 g (75% of theory) of ethyl 4-(difluoromethyl)-1-methyl-1H-pyrazole-3-carboxylate having a melting point of 30-31° C. were obtained.

¹H NMR (CDCl₃): δ=1.37 (t, 3H); 4.07 (t, 3H); 4.31 (q, CH₂); 7.49 (t, CF₂H); 7.86 (s, 1H) ppm. ¹⁹F NMR (CDCl₃): δ=−117.2 (d, J=54.7 Hz) ppm. 

1-17. (canceled)
 18. A process for preparing fluoromethyl-substituted heterocycles of formula (I)

in which R¹ is hydrogen, fluorine, or chlorine, R² is hydrogen, fluorine, or chlorine, R³ is C₁-C₆-alkyl, A is a 5-membered heterocycle selected from the group consisting of pyrazole that is substituted by R⁴ in the 1-position, thiazole that is substituted by R⁴ in the 2-position, and oxazole that is substituted by R⁴ in the 2-position, and R⁴ is C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-alkylthio-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, or phenyl, comprising converting a chloromethyl-substituted heterocycle of formula (II)

in which R¹, R², R³, and A are each as defined for formula (I), to a fluoromethyl-substituted heterocycle of formula (I) in the presence of a fluorinating agent and optionally in the presence of a diluent.
 19. A process according to claim 18 wherein for the chloromethyl-substituted heterocycle of formula (II), R¹ is hydrogen, fluorine, or chlorine, R² is hydrogen, fluorine, or chlorine, R³ is C₁-C₄-alkyl, A is a 5-membered heterocycle selected from the group consisting of

 where in each case the bond marked by * is joined to the —CClR¹R² group and the other bond is joined to the CO₂R³ ester group, and R⁴ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, or phenyl.
 20. A process according to claim 18 wherein the chloromethyl-substituted heterocycle of formula (II) is selected from the group consisting of compounds of formulas (II-a), (II-b), (II-c), and (II-d)

in which R¹, R², and R³ are as defined in claim
 18. 21. A process according to claim 20 in which R¹ is chlorine, R² is hydrogen, and R³ is methyl or ethyl.
 22. A process according to claim 18 wherein the fluorinating agent is an alkali metal fluoride, cobalt(III) fluoride, halogen fluoride, antimony fluoride, molybdenum fluoride, hydrogen fluoride, hydrogen fluoride/pyridine mixture, a tertiary ammonium hydrofluoride, or a trialkylamine hydrofluoride of the formula n HF/N(Alk)₃ in which n is 1, 2, or 3, and Alk is C₁-C₄-alkyl.
 23. A process according to claim 18 wherein the fluorinating agent is 3 HF/N(Et)₃ (Franz reagent), 3 HF/N(n-Bu)₃, or HF/pyridine (Olah's reagent).
 24. A process according to claim 18 wherein the fluorinating agent is 3 HF/N(Et)₃ (Franz reagent) or 3 HF/N(n-Bu)₃.
 25. A process according to claim 18 that it is carried out at a temperature of 80° C. to 170° C.
 26. A process according to claim 18 that it is carried out at a temperature of 120° C. to 150° C.
 27. A process for preparing a fungicidally active carboxamide of formula (VII)

in which R¹ is hydrogen, fluorine, or chlorine, R² is hydrogen, fluorine, or chlorine, A is a 5-membered heterocycle selected from the group consisting of pyrazole that is substituted by R⁴ in the 1-position, thiazole that is substituted by R⁴ in the 2-position, and oxazole that is substituted by R⁴ in the 2-position, R⁴ is C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-alkylthio-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, or phenyl, R⁷ is hydrogen, C₁-C₈-alkyl, C₁-C₆-alkylsulphinyl, C₁-C₆-alkylsulphonyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, or C₃-C₈-cycloalkyl; is C₁-C₆-haloalkyl, C₁-C₄-haloalkylthio, C₁-C₄-haloalkylsulphinyl, C₁-C₄-haloalkylsulphonyl, halo-C₁-C₄-alkoxy-C₁-C₄-alkyl, or C₃-C₈-halocycloalkyl having in each case 1 to 9 fluorine, chlorine, and/or bromine atoms; is formyl, formyl-C₁-C₃-alkyl, (C₁-C₃-alkyl)carbonyl-C₁-C₃-alkyl, or (C₁-C₃-alkoxy)carbonyl-C₁-C₃-alkyl; is halo-(C₁-C₃-alkyl)carbonyl-C₁-C₃-alkyl or halo-(C₁-C₃-alkoxy)carbonyl-C₁-C₃-alkyl having in each case 1 to 13 fluorine, chlorine, and/or bromine atoms; is (C₁-C₈-alkyl)carbonyl, (C₁-C₈-alkoxy)carbonyl, (C₁-C₄-alkoxy-C₁-C₄-alkyl)carbonyl, or (C₃-C₈-cycloalkyl)carbonyl; is (C₁-C₆-haloalkyl)carbonyl, (C₁-C₆-haloalkoxy)-carbonyl, (halo-C₁-C₄-alkoxy-C₁-C₄-alkyl)carbonyl, or (C₃-C₈-halo-cycloalkyl)carbonyl having in each case 1 to 9 fluorine, chlorine, and/or bromine atoms; or is —C(═O)C(═O)R¹⁰, —CONR¹¹R¹², or —CH₂NR¹³R¹⁴, R⁸ is hydrogen, fluorine, chlorine, methyl, isopropyl, methylthio, or trifluoromethyl, n is 1, 2, 3 or 4, R⁹ is optionally mono- to pentasubstituted phenyl having identical or different substituents selected from the group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₂-haloalkyl, and C₁-C₂-haloalkoxy having in each case 1 to 5 fluorine, chlorine, and/or bromine atoms, hydroxyimino-C₁-C₄-alkyl, C₁-C₄-alkoxyimino-C₁-C₄-alkyl, C₁-C₄-halo-alkoxyimino-C₁-C₄-alkyl, and, when substituted with two adjacent substituents, difluoromethylenedioxy or tetrafluoroethylenedioxy; is C₃-₁₀-cycloalkyl or C₃-C₁₀-bicycloalkyl that is in each case optionally mono- to tetrasubstituted, identically or differently, by halogen and/or C₁-C₄-alkyl; is unsubstituted C₂-C₂₀-alkyl, or C₁-C₂₀-alkyl that is mono- or polysubstituted, identically or differently, by fluorine, chlorine, bromine, iodine, and/or C₃-C₆-cycloalkyl in which case the cycloalkyl moiety is itself optionally mono- to tetrasubstituted, identically or differently, by fluorine, chlorine, bromine, iodine, C₁-C₄-alkyl, and/or C₁-C₄-haloalkyl; or is C₂-C₂₀-alkenyl or C₂-C₂₀-alkynyl that is in each case optionally mono- or polysubstituted, identically or differently, by fluorine, chlorine, bromine, iodine, and/or C₃-C₆-cycloalkyl in which the cycloalkyl moiety is itself optionally mono- to tetrasubstituted, identically or differently, by fluorine, chlorine, bromine, iodine, C₁-C₄-alkyl, and/or C₁-C₄-haloalkyl, R¹⁰ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, or C₃-C₈-cycloalkyl; or is C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, halo-C₁-C₄-alkoxy-C₁-C₄-alkyl, or C₃-C₈-halocycloalkyl having in each case 1 to 9 fluorine, chlorine, and/or bromine atoms, R¹¹ and R¹² are each independently hydrogen, C₁-C₈-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, or C₃-C₈-cycloalkyl; or are each independently C₁-C₈-haloalkyl, halo-C₁-C₄-alkoxy-C₁-C₄-alkyl, or C₃-C₈-halocycloalkyl having in each case 1 to 9 fluorine, chlorine and/or bromine atoms; or R¹¹ and R¹², together with the nitrogen atom to which they are bonded, are a saturated heterocycle having 5 to 8 ring atoms that is optionally mono- or polysubstituted, identically or differently, by halogen or C₁-C₄-alkyl, and in which the heterocycle optionally contains 1 or 2 additional nonadjacent heteroatoms selected from the group of oxygen, sulphur, and NR¹⁵, R¹³ and R¹⁴ are each independently hydrogen, C₁-C₈-alkyl, or C₃-C₈-cycloalkyl; or are each independently C₁-C₈-haloalkyl or C₃-C₈-halocycloalkyl having in each case 1 to 9 fluorine, chlorine, and/or bromine atoms; or R¹³ and R¹⁴, together with the nitrogen atom to which they are bonded, are a saturated heterocycle having 5 to 8 ring atoms that is optionally mono- or polysubstituted, identically or differently, by halogen or C₁-C₄-alkyl, and in which the heterocycle optionally contains 1 or 2 additional nonadjacent heteroatoms selected from the group of oxygen, sulphur, and NR¹⁵, and R¹⁵ is hydrogen or C₁-C₆-alkyl, comprising (1) hydrolyzing a fluoromethyl-substituted heterocycle of formula (I)

 in which R¹, R², and A are each as defined for formula (VII), and R³ is C₁-C₆-alkyl, in the presence of a base and optionally in the presence of a diluent, to form a free acid, and (2) subsequently either (i) converting the free acid to the corresponding acid chloride in the presence of a chlorinating agent and optionally in the presence of a diluent, or (ii) reacting the free acid directly with an aniline derivative of the formula (VIII)

 in which R⁷, R⁸, n and R⁹ are each as defined for formula (VII), optionally in the presence of a catalyst, optionally in the presence of a condensing agent, optionally in the presence of an acid binding agent, and optionally in the presence of a diluent.
 28. A process according to claim 27 wherein the compound of formula (I) is obtained by reacting a chloromethyl-substituted heterocycle of formula (II)

in which R¹ is hydrogen, fluorine, or chlorine, R² is hydrogen, fluorine, or chlorine, R³ is C₁-C₆-alkyl, and A is a 5-membered heterocycle selected from the group consisting of pyrazole that is substituted by R⁴ in the 1-position, thiazole that is substituted by R⁴ in the 2-position, and oxazole that is substituted by R⁴ in the 2-position, with a fluorinating agent, optionally in the presence of a diluent.
 29. A chloromethyl-substituted heterocycle of formula (II)

in which R¹ is hydrogen, fluorine, or chlorine, R² is hydrogen, fluorine, or chlorine, R³ is C₁-C₆-alkyl, and A is a 5-membered heterocycle selected from the group consisting of pyrazole that is substituted by R⁴ in the 1-position, thiazole that is substituted by R⁴ in the 2-position, and oxazole that is substituted by R⁴ in the 2-position.
 30. A compound of formula (II-a)

in which R¹ is hydrogen, fluorine, or chlorine, R² is hydrogen, fluorine, or chlorine, and R³ is C₁-C₆-alkyl.
 31. A compound of formula (II-b)

in which R¹ is hydrogen, fluorine, or chlorine, R² is hydrogen, fluorine, or chlorine, and R³ is C₁-C₆-alkyl.
 32. A compound of formula (II-c)

in which R¹ is hydrogen, fluorine, or chlorine, R² is hydrogen, fluorine, or chlorine, and R³ is C₁-C₆-alkyl.
 33. A compound of formula (II-d)

in which R¹ is hydrogen, fluorine, or chlorine, R² is hydrogen, fluorine, or chlorine, and R³ is C₁-C₆-alkyl. 